Potency and pharmacokinetic enhancement of D-Peptide HIV-1 entry inhibitors

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Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Redman, Joseph Stapley
Title Potency and pharmacokinetic enhancement of D-Peptide HIV-1 entry inhibitors
Date 2012-12
Description Peptides are a powerful class of therapeutics with high potency, high specificity, low immunogenicity, and effective methods of discovery. However, peptides often possess limitations including degradation by proteases, rapid clearance by renal filtration, and difficulty passing through membranes. The Kay lab at the University of Utah has applied the benefits of peptide design to tackling the problem of HIV-1 transmission. In this dissertation I describe the discovery of our lead peptide candidate, PIE12, including its optimization by mirror-image phage display, its potency enhancement by defined geometric linkages and lipid conjugation, its engineered ability to prevent HIV-1 resistance, and finally the optimization of its pharmacokinetic properties. These efforts have overcome the common limitations of peptide therapeutics and produced an ideal preclinical candidate for the treatment and prevention of HIV/AIDS. The first chapter examines the scope of the HIV pandemic, describes HIV-1's susceptible target for which we developed PIE12, and includes a brief examination of the current state of the peptide therapeutic field. The second chapter reviews methods of peptide discovery that enable protease resistance, including a discussion of well-validated techniques like mirror-image phage display followed by a review of several emerging technologies. The third chapter reveals how the aforementioned techniques were utilized in the discovery of PIE12, including early efforts to link PIE12 peptides together in order to improve potency. The fourth chapter completes this story, illuminating our efforts to optimize the linkages between PIE12 peptides in order to increase potency, and includes information on potency-enhancing membrane-tethering moieties. The fifth chapter describes our efforts to make potent PIE12-conjugates suitable for subcutaneous delivery, including new conjugate designs and detailed evaluation of their half-life-improving properties. The final chapter discusses future directions and new opportunities revealed to us by the body of this work. iv
Is Part of do not permission
Type Text
Publisher University of Utah
Subject MESH Acquired Immunodeficiency Syndrome; HIV Infections; HIV-1; Peptides; Peptide Library; Protease Inhibitors; Pharmacokinetics; HIV Fusion Inhibitors; Binding Sites; Peptide Hydrolases; Anti-HIV Agents; Drug Design; Drug Resistance; Drug Delivery Systems; Half-Life; Recombinant Proteins
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Potency and Pharmacokinetic Enhancement of D-Peptide HIV-1 Entry Inhibitors
Rights Management Copyright © Joseph Stapley Redman 2012
Format Medium application/pdf
Format Extent 8,236,622 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s60c59nf
Setname ir_etd
ID 196051
Reference URL https://collections.lib.utah.edu/ark:/87278/s60c59nf
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